PYRIDO-[3,4-d]PYRIDAZINE AMINE DERIVATIVES USEFUL AS NLRP3 DERIVATIVES

ABSTRACT

The present disclosure relates to inhibitors of NLRP3 useful in the treatment of diseases and disorders inhibited by said protein.

CROSS-REFERENCE RELATED APPLICATION

This application is a continuation application of U.S. patentapplication Ser. No. 17/704,983, filed Mar. 25, 2022, the contents ofwhich is herein incorporated by reference in its entirety.

FIELD OF INVENTION

The present invention is directed to inhibitors of NLR family pyrindomain containing 3 (NLRP3) proteins. The inhibitors described hereinare useful in the treatment of diseases and disorders associated withthe modulation of NLRP3 proteins. In particular, the invention isconcerned with compounds and pharmaceutical compositions inhibitingNLRP3, methods of treating diseases and disorders associated with NLRP3using said compounds and pharmaceutical compositions, and methods ofsynthesizing said compounds and compositions.

BACKGROUND OF INVENTION

Innate immune responses are mediated by different types of receptorstermed pattern-recognition receptors (PRRs). PRRs recognize the presenceof pathogen-associated molecular patterns (PAMPs) and damage-associatedmolecular patterns (DAMPs). Once engaged these receptors trigger theactivation of downstream inflammatory pathways that will help resolveinjury. However, in many instances this activation can be uncontrolledand leads to disease.

The inflammasomes represent a class of PRRs that are crucial componentsof the innate immune response. Activation of the inflammasomes trigger acascade of events that releases IL-1β, IL-18, and promotes aninflammatory form of cell death called pyroptosis induced by theactivation of Gasdermin. Pyroptosis is a unique form of inflammatorycell death that leads to the release of not only cytokines but alsoother intracellular components that promote a broader immune responseboth of the innate and acquired immune system. Thus, inflammasomeactivation is a major regulatory of the inflammatory cascade.

NLRP3 is the most characterized inflammasome and has been shown to becritical in innate immunity and inflammatory responses. While severalother NLR complexes, such as NLRC4, are activated under very specificcircumstances, NLRP3 can be activated by numerous stimuli and should beseen as a sensor of intracellular homeostatic imbalance. Therefore, itsprecise functioning is essential. In addition to playing a role in hostimmune defense, dysregulation of NLRP3 has been linked to thepathogenesis of many inflammatory disorders.

These include genetic diseases such as cryopyrin-associated periodicsyndromes (CAPS) which is caused by gain-of-function mutations in theNLRP3 gene, as well as many prevalent neurologic and systemic diseases.Importantly, NLRP3 hyperactivation has been demonstrated pre-clinicallyto play a critical role in a plethora of inflammatory and degenerativediseases including, NASH, atherosclerosis and other cardiovasculardiseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, andnumerous other autoinflammatory diseases. Thus, there is an unmet needin the field to develop small molecules for modulating NLRP3 activity totreat various diseases and disorders.

SUMMARY OF INVENTION

In a first aspect, the present disclosure provides, inter alia, suitablecompounds selected from:

-   (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;-   5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;-   (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;-   (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;-   (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol;    and-   (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

and pharmaceutically acceptable salts, solvates, clathrates, hydrates,stereoisomers, or tautomers thereof.

Another aspect of the disclosure relates to pharmaceutical compositionscomprising(R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenolor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.

Another aspect of the disclosure relates to pharmaceutical compositionscomprising5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenolor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.

Another aspect of the disclosure relates to pharmaceutical compositionscomprising(R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenolor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.

Another aspect of the disclosure relates to pharmaceutical compositions(S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenolor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.

Another aspect of the disclosure relates to pharmaceutical compositionscomprising(R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenolor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.

Another aspect of the disclosure relates to pharmaceutical compositionscomprising(S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenolor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.

In some aspects, the present disclosure provides compounds obtainableby, or obtained by, a method for preparing a compound as describedherein (e.g., a method comprising one or more steps described in Schemes1 and 2).

In some aspects, the present disclosure provides pharmaceuticalcompositions comprising a compound of the present disclosure, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.

In some aspects, the present disclosure provides an intermediate asdescribed herein, being suitable for use in a method for preparing acompound as described herein (e.g., the intermediate is selected fromthe intermediates described in Examples 1 and 2.

In some aspects, the present disclosure provides a method of treating orpreventing a disease or disorder disclosed herein in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of the present disclosure or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the present disclosure.

In some aspects, the present disclosure provides a method of treating adisease or disorder disclosed herein in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of the presentdisclosure.

In some aspects, the present disclosure provides a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof for usein treating or preventing a disease or disorder disclosed herein.

In some aspects, the present disclosure provides a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof for usein treating a disease or disorder disclosed herein.

In some aspects, the present disclosure provides use of a compound ofthe present disclosure or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for treating or preventing a disease ordisorder disclosed herein.

In some aspects, the present disclosure provides use of a compound ofthe present disclosure or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for treating a disease or disorderdisclosed herein.

In some aspects, the present disclosure provides a method of treating orpreventing an NLRP3-related disease or disorder selected fromParkinson's disease, Alzheimer's disease, multiple sclerosis, refractoryepilepsy, stroke, ALS, headache/pain, and traumatic brain injury.

The method comprises administering to the subject at least onetherapeutically effective amount of the compound disclosed herein.

In some embodiments, the disease or disorder is inflammation, anauto-immune disease, a cancer, an infection, a disease or disorder ofthe central nervous system, a metabolic disease, a cardiovasculardisease, a respiratory disease, a kidney disease, a liver disease, anocular disease, a skin disease, a lymphatic disease, a rheumaticdisease, a psychological disease, graft versus host disease, allodynia,or an NLRP3-related disease in a subject that has been determined tocarry a germline or somatic non-silent mutation in NLRP3.

In some embodiments, the disease or disorder of the central nervoussystem is Parkinson's disease, Alzheimer's disease, traumatic braininjury, spinal cord injury, amyotrophic lateral sclerosis, or multiplesclerosis.

In some embodiments, the kidney disease is an acute kidney disease, achronic kidney disease, or a rare kidney disease.

In some embodiments, the skin disease is psoriasis, hidradenitissuppurativa (HS), or atopic dermatitis.

In some embodiments, the rheumatic disease is dermatomyositis, Still'sdisease, or juvenile idiopathic arthritis.

In some embodiments, the NLRP3-related disease in a subject that hasbeen determined to carry a germline or somatic non-silent mutation inNLRP3 is cryopyrin-associated autoinflammatory syndrome.

In some embodiments, the cryopyrin-associated autoinflammatory syndromeis familial cold autoinflammatory syndrome, Muckle-Wells syndrome, orneonatal onset multisystem inflammatory disease.

In some aspects, the present disclosure provides a method of preparing acompound of the present disclosure.

In some aspects, the present disclosure provides a method of preparing acompound, comprising one or more steps described herein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods and examples areillustrative only and are not intended to be limiting. In the case ofconflict between the chemical structures and names of the compoundsdisclosed herein, the chemical structures will control.

Other features and advantages of the disclosure will be apparent fromthe following detailed description and claims.

DETAILED DESCRIPTION OF INVENTION

The present disclosure relates to phthalazine derivatives,pharmaceutically acceptable salts, solvates, clathrates, hydrates,single stereoisomers, mixtures of stereoisomers, or racemic mixtures ofstereoisomers thereof, which may inhibit NLRP3 activity and areaccordingly useful in methods of treatment of the human or animal body.Compounds of this invention demonstrate surprising and unexpectedsuperiority over their brain penetration. The present disclosure alsorelates to processes for the preparation of these compounds, topharmaceutical compositions comprising them and to their use in thetreatment of disorders in which NLRP3 is implicated, such asinflammation, an auto-immune disease, a cancer, an infection, a diseaseor disorder of the central nervous system, a metabolic disease, acardiovascular disease, a respiratory disease, a kidney disease, a liverdisease, an ocular disease, a skin disease, a lymphatic disease, arheumatic disease, a psychological disease, graft versus host disease,allodynia, or an NLRP3-related disease in a subject that has beendetermined to carry a germline or somatic non-silent mutation in NLRP3.

Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the following meanings set out below.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchformula. Combinations of substituents and/or variables are permissible,but only if such combinations result in stable compounds.

When any variable (e.g., R) occurs more than one time in any constituentor formula for a compound, its definition at each occurrence isindependent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R moieties, thenthe group may optionally be substituted with up to two R moieties and Rat each occurrence is selected independently from the definition of R.Also, combinations of substituents and/or variables are permissible, butonly if such combinations result in stable compounds.

It is to be understood that the present disclosure provides methods forthe synthesis of the compounds of any of the Formulae described herein.The present disclosure also provides detailed methods for the synthesisof various disclosed compounds of the present disclosure according tothe following schemes as well as those shown in the Examples.

It is to be understood that, throughout the description, wherecompositions are described as having, including, or comprising specificcomponents, it is contemplated that compositions also consistessentially of, or consist of, the recited components. Similarly, wheremethods or processes are described as having, including, or comprisingspecific process steps, the processes also consist essentially of, orconsist of, the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions is immaterial so long as the invention remains operable.Moreover, two or more steps or actions can be conducted simultaneously.

It is to be understood that the synthetic processes of the disclosurecan tolerate a wide variety of functional groups, therefore varioussubstituted starting materials can be used. The processes generallyprovide the desired final compound at or near the end of the overallprocess, although it may be desirable in certain instances to furtherconvert the compound to a pharmaceutically acceptable salt thereof.

It is to be understood that compounds of the present disclosure can beprepared in a variety of ways using commercially available startingmaterials, compounds known in the literature, or from readily preparedintermediates, by employing standard synthetic methods and procedureseither known to those skilled in the art, or which will be apparent tothe skilled artisan in light of the teachings herein. Standard syntheticmethods and procedures for the preparation of organic molecules andfunctional group transformations and manipulations can be obtained fromthe relevant scientific literature or from standard textbooks in thefield. Although not limited to any one or several sources, classic textssuch as Smith, M. B., March, J., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons:New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups inOrganic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L.Fieser and M. Fieser, Fieser and Fieser's Reagents for OrganicSynthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), incorporated by reference herein, are useful and recognisedreference textbooks of organic synthesis known to those in the art

One of ordinary skill in the art will note that, during the reactionsequences and synthetic schemes described herein, the order of certainsteps may be changed, such as the introduction and removal of protectinggroups. One of ordinary skill in the art will recognise that certaingroups may require protection from the reaction conditions via the useof protecting groups. Protecting groups may also be used todifferentiate similar functional groups in molecules. A list ofprotecting groups and how to introduce and remove these groups can befound in Greene, T. W., Wuts, P. G. M., Protective Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons: New York, 1999.

It is to be understood that, unless otherwise stated, any description ofa method of treatment or prevention includes use of the compounds toprovide such treatment or prevention as is described herein. It is to befurther understood, unless otherwise stated, any description of a methodof treatment or prevention includes use of the compounds to prepare amedicament to treat or prevent such condition. The treatment orprevention includes treatment or prevention of human or non-humananimals including rodents and other disease models.

It is to be understood that, unless otherwise stated, any description ofa method of treatment includes use of the compounds to provide suchtreatment as is described herein. It is to be further understood, unlessotherwise stated, any description of a method of treatment includes useof the compounds to prepare a medicament to treat such condition. Thetreatment includes treatment of human or non-human animals includingrodents and other disease models. As used herein, the term “subject” isinterchangeable with the term “subject in need thereof”, both of whichrefer to a subject having a disease or having an increased risk ofdeveloping the disease. A “subject” includes a mammal. The mammal can bee.g., a human or appropriate non-human mammal, such as primate, mouse,rat, dog, cat, cow, horse, goat, camel, sheep or a pig. In oneembodiment, the mammal is a human. A subject in need thereof can be onewho has been previously diagnosed or identified as having a disease ordisorder disclosed herein. A subject in need thereof can also be one whois suffering from a disease or disorder disclosed herein.

Alternatively, a subject in need thereof can be one who has an increasedrisk of developing such disease or disorder relative to the populationat large (i.e., a subject who is predisposed to developing such disorderrelative to the population at large). A subject in need thereof can havea refractory or resistant a disease or disorder disclosed herein (i.e.,a disease or disorder disclosed herein that does not respond or has notyet responded to treatment). The subject may be resistant at start oftreatment or may become resistant during treatment. In some embodiments,the subject in need thereof received and failed all known effectivetherapies for a disease or disorder disclosed herein. In someembodiments, the subject in need thereof received at least one priortherapy.

As used herein, the term “treating” or “treat” describes the managementand care of a patient for the purpose of combating a disease, condition,or disorder and includes the administration of a compound of the presentdisclosure, or a pharmaceutically acceptable salt, polymorph or solvatethereof, to alleviate the symptoms or complications of a disease,condition or disorder, or to eliminate the disease, condition ordisorder. The term “treat” can also include treatment of a cell in vitroor an animal model. It is to be appreciated that references to“treating” or “treatment” include the alleviation of establishedsymptoms of a condition. “Treating” or “treatment” of a state, disorderor condition therefore includes: (1) preventing or delaying theappearance of clinical symptoms of the state, disorder or conditiondeveloping in a human that may be afflicted with or predisposed to thestate, disorder or condition but does not yet experience or displayclinical or subclinical symptoms of the state, disorder or condition,(2) inhibiting the state, disorder or condition, i.e., arresting,reducing or delaying the development of the disease or a relapse thereof(in case of maintenance treatment) or at least one clinical orsubclinical symptom thereof, or (3) relieving or attenuating thedisease, i.e., causing regression of the state, disorder or condition orat least one of its clinical or subclinical symptoms.

It is to be understood that a compound of the present disclosure, or apharmaceutically acceptable salt, polymorph or solvate thereof, can ormay also be used to prevent a relevant disease, condition or disorder,or used to identify suitable candidates for such purposes.

As used herein, the term “preventing,” “prevent,” or “protectingagainst” describes reducing or eliminating the onset of the symptoms orcomplications of such disease, condition or disorder.

It is to be understood that one skilled in the art may refer to generalreference texts for detailed descriptions of known techniques discussedherein or equivalent techniques. These texts include Ausubel et al.,Current Protocols in Molecular Biology, John Wiley and Sons, Inc.(2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000);Coligan et al., Current Protocols in Immunology, John Wiley & Sons,N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons,N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975),Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA,18th edition (1990). These texts can, of course, also be referred to inmaking or using an aspect of the disclosure.

It is to be understood that the present disclosure also providespharmaceutical compositions comprising any compound described herein incombination with at least one pharmaceutically acceptable excipient orcarrier.

As used herein, the term “pharmaceutical composition” is a formulationcontaining the compounds of the present disclosure in a form suitablefor administration to a subject. In one embodiment, the pharmaceuticalcomposition is in bulk or in unit dosage form. The unit dosage form isany of a variety of forms, including, for example, a capsule, an IV bag,a tablet, a single pump on an aerosol inhaler or a vial. The quantity ofactive ingredient (e.g., a formulation of the disclosed compound orsalt, hydrate, solvate or isomer thereof) in a unit dose of compositionis an effective amount and is varied according to the particulartreatment involved. One skilled in the art will appreciate that it issometimes necessary to make routine variations to the dosage dependingon the age and condition of the patient. The dosage will also depend onthe route of administration. A variety of routes are contemplated,including oral, pulmonary, rectal, parenteral, transdermal,subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational,buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.Dosage forms for the topical or transdermal administration of a compoundof this disclosure include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. In one embodiment, theactive compound is mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that are required.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, anions, cations, materials, compositions, carriers, and/ordosage forms which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of human beings and animalswithout excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

As used herein, the term “pharmaceutically acceptable excipient” meansan excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes excipient that is acceptable for veterinaryuse as well as human pharmaceutical use. A “pharmaceutically acceptableexcipient” as used in the specification and claims includes both one andmore than one such excipient.

It is to be understood that a pharmaceutical composition of thedisclosure is formulated to be compatible with its intended route ofadministration. Examples of routes of administration include parenteral,e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion),inhalation, transdermal (topical), and transmucosal administration.Solutions or suspensions used for parenteral, intradermal, orsubcutaneous application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens: antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates, and agents for the adjustment oftonicity such as sodium chloride or dextrose. The pH can be adjustedwith acids or bases, such as hydrochloric acid or sodium hydroxide. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic.

It is to be understood that a compound or pharmaceutical composition ofthe disclosure can be administered to a subject in many of thewell-known methods currently used for chemotherapeutic treatment. Forexample, a compound of the disclosure may be injected into the bloodstream or body cavities or taken orally or applied through the skin withpatches. The dose chosen should be sufficient to constitute effectivetreatment but not so high as to cause unacceptable side effects. Thestate of the disease condition (e.g., a disease or disorder disclosedherein) and the health of the patient should preferably be closelymonitored during and for a reasonable period after treatment.

As used herein, the term “therapeutically effective amount”, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician.

It is to be understood that, for any compound, the therapeuticallyeffective amount can be estimated initially either in cell cultureassays, e.g., of neoplastic cells, or in animal models, usually rats,mice, rabbits, dogs, or pigs. The animal model may also be used todetermine the appropriate concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Therapeutic/prophylacticefficacy and toxicity may be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., ED₅₀ (thedose therapeutically effective in 50% of the population) and LD₅₀ (thedose lethal to 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index, and it can be expressed asthe ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit largetherapeutic indices are desired. The dosage may vary within this rangedepending upon the dosage form employed, sensitivity of the patient, andthe route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy.

The pharmaceutical compositions containing active compounds of thepresent disclosure may be manufactured in a manner that is generallyknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilising processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol and sorbitol, and sodium chloridein the composition. Prolonged absorption of the injectable compositionscan be brought about by including in the composition an agent whichdelays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilisation. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebuliser.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the disclosure are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the disclosure vary depending onthe agent, the age, weight, and clinical condition of the recipientpatient, and the experience and judgment of the clinician orpractitioner administering the therapy, among other factors affectingthe selected dosage. Generally, the dose should be sufficient to resultin slowing, and preferably regressing, the symptoms of the disease ordisorder disclosed herein and also preferably causing completeregression of the disease or disorder. Dosages can range from about 0.01mg/kg per day to about 5000 mg/kg per day. An effective amount of apharmaceutical agent is that which provides an objectively identifiableimprovement as noted by the clinician or other qualified observer.Improvement in survival and growth indicates regression. As used herein,the term “dosage effective manner” refers to amount of an activecompound to produce the desired biological effect in a subject or cell.

It is to be understood that the pharmaceutical compositions can beincluded in a container, pack, or dispenser together with instructionsfor administration.

It is to be understood that, for the compounds of the present disclosurebeing capable of further forming salts, all of these forms are alsocontemplated within the scope of the claimed disclosure.

As used herein, the term “pharmaceutically acceptable salts” refer toderivatives of the compounds of the present disclosure wherein theparent compound is modified by making acid or base salts thereof.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines, alkali or organic salts of acidic residues such as carboxylicacids, and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include, but arenot limited to, those derived from inorganic and organic acids selectedfrom 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic,benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic,pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic,salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric,tannic, tartaric, toluene sulfonic, and the commonly occurring amineacids, e.g., glycine, alanine, phenylalanine, arginine, etc.

In some embodiments, the pharmaceutically acceptable salt is a sodiumsalt, a potassium salt, a calcium salt, a magnesium salt, a diethylaminesalt, a choline salt, a meglumine salt, a benzathine salt, atromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

Other examples of pharmaceutically acceptable salts include hexanoicacid, cyclopentane propionic acid, pyruvic acid, malonic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonicacid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, muconic acid, and the like. The present disclosure alsoencompasses salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like. In the salt form, it isunderstood that the ratio of the compound to the cation or anion of thesalt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or1:3.

It is to be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same salt.

The compounds, or pharmaceutically acceptable salts thereof, areadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperitoneally, subcutaneously,intramuscularly, intravenously, rectally, intrapleurally, intrathecallyand parenterally. In one embodiment, the compound is administeredorally. One skilled in the art will recognise the advantages of certainroutes of administration.

The dosage regimen utilising the compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counter,or arrest the progress of the condition. An ordinarily skilled physicianor veterinarian can readily determine and prescribe the effective amountof the drug required to counter or arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compoundsof the disclosure can be found in Remington: the Science and Practice ofPharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In anembodiment, the compounds described herein, and the pharmaceuticallyacceptable salts thereof, are used in pharmaceutical preparations incombination with a pharmaceutically acceptable carrier or diluent.Suitable pharmaceutically acceptable carriers include inert solidfillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present disclosure areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentdisclosure. The examples do not limit the claimed disclosure. Based onthe present disclosure the skilled artisan can identify and employ othercomponents and methodology useful for practicing the present disclosure.

In the synthetic schemes described herein, compounds may be drawn withone particular configuration for simplicity. Such particularconfigurations are not to be construed as limiting the disclosure to oneor another isomer, tautomer, regioisomer or stereoisomer, nor does itexclude mixtures of isomers, tautomers, regioisomers or stereoisomers;however, it will be understood that a given isomer, tautomer,regioisomer or stereoisomer may have a higher level of activity thananother isomer, tautomer, regioisomer or stereoisomer.

All publications and patent documents cited herein are incorporatedherein by reference as if each such publication or document wasspecifically and individually indicated to be incorporated herein byreference. Citation of publications and patent documents is not intendedas an admission that any is pertinent prior art, nor does it constituteany admission as to the contents or date of the same. The inventionhaving now been described by way of written description, those of skillin the art will recognize that the invention can be practiced in avariety of embodiments and that the foregoing description and examplesbelow are for purposes of illustration and not limitation of the claimsthat follow.

As use herein, the phrase “compound of the disclosure” refers to thosecompounds which are disclosed herein, both generically and specifically.

Compounds of the Present Disclosure

In one aspect, the present disclosure provides, inter alia, compoundsselected from

-   (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;-   5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;-   (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;-   (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;-   (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol;    and-   (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

In some embodiments, the compound is(R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

In some embodiments, the compound is5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

In some embodiments, the compound is(R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

In some embodiments, the compound is(S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

In some embodiments, the compound is(R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

In some embodiments, the compound is(S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

In some embodiments, the compound is a pharmaceutically acceptable saltof any one of the compounds described herein.

In some aspects, the present disclosure provides a compound being anisotopic derivative (e.g., isotopically labeled compound) of any one ofthe compounds of the Formulae disclosed herein.

In some embodiments, the compound is an isotopic derivative of any oneof the compounds described herein and prodrugs and pharmaceuticallyacceptable salts thereof.

In some embodiments, the compound is an isotopic derivative of any oneof the compounds described herein and pharmaceutically acceptable saltsthereof.

In some embodiments, the compound is an isotopic derivative of any oneof prodrugs of the compounds described herein and pharmaceuticallyacceptable salts thereof.

In some embodiments, the compound is an isotopic derivative of any oneof the compounds described herein.

It is understood that the isotopic derivative can be prepared using anyof a variety of art-recognised techniques. For example, the isotopicderivative can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples described herein, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

In some embodiments, the isotopic derivative is a deuterium labeledcompound.

In some embodiments, the isotopic derivative is a deuterium labeledcompound of any one of the compounds of the Formulae disclosed herein.

The term “isotopic derivative”, as used herein, refers to a derivativeof a compound in which one or more atoms are isotopically enriched orlabelled. For example, an isotopic derivative of a compound disclosedherein is isotopically enriched with regard to, or labelled with, one ormore isotopes as compared to the corresponding disclosed compound. Insome embodiments, the isotopic derivative is enriched with regard to, orlabelled with, one or more atoms selected from ²H, ³C, ¹⁴C, ¹⁵N, ¹⁸O,²⁹Si, ³¹P, and ³⁴S. In some embodiments, the isotopic derivative is adeuterium labeled compound (i.e., being enriched with ²H with regard toone or more atoms thereof). In some embodiments, the compound is a ¹⁸Flabeled compound. In some embodiments, the compound is a ¹²³I labeledcompound, a ¹²¹I labeled compound, a ¹²⁵I labeled compound, a ¹²⁹Ilabeled compound, a ¹³¹I labeled compound, a ¹³⁵I labeled compound, orany combination thereof. In some embodiments, the compound is a ³³Slabeled compound, a ³⁴S labeled compound, a ³⁵S labeled compound, a ³⁶Slabeled compound, or any combination thereof.

It is understood that the ¹⁸F, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I, ¹³¹I, ¹³⁵I, ³²S,³⁴S, ³⁵S, and/or ³⁶S labeled compound, can be prepared using any of avariety of art-recognised techniques. For example, the deuterium labeledcompound can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples described herein, bysubstituting a ¹⁸F, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I, ¹³¹I, ¹³⁵I, ³²S, ³⁴S, ³⁵S,and/or ³⁶S labeled reagent for a non-isotope labeled reagent.

A compound of the invention or a pharmaceutically acceptable salt orsolvate thereof that contains one or more of the aforementioned ¹⁸F,¹²³I, ¹²⁴, ¹²⁵I, ¹²⁹I, ¹³¹I, ³²S, ³⁴S, ³⁵S, and ³⁶S atom(s) is withinthe scope of the invention. Further, substitution with isotope (e.g.,¹⁸F, ²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I, ¹³¹I, ¹³⁵I, ³²S, ³³S, ³⁵S, and/or ³⁶S) mayafford certain therapeutic advantages resulting from greater metabolicstability, e.g., increased in vivo half-life or reduced dosagerequirements.

For the avoidance of doubt it is to be understood that, where in thisspecification a group is qualified by “described herein”, the said groupencompasses the first occurring and broadest definition as well as eachand all of the particular definitions for that group.

A suitable pharmaceutically acceptable salt of a compound of thedisclosure is, for example, an acid-addition salt of a compound of thedisclosure which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric methane sulfonate or maleic acid. In addition, a suitablepharmaceutically acceptable salt of a compound of the disclosure whichis sufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a pharmaceutically acceptable cation, for example a salt withmethylamine, dimethylamine, diethylamine, trimethylamine, piperidine,morpholine or tris-(2-hydroxyethyl)amine.

It will be understood that the compounds of any one of the Formulaedisclosed herein and any pharmaceutically acceptable salts thereof,comprise stereoisomers, mixtures of stereoisomers, polymorphs of allisomeric forms of said compounds.

As used herein, the term “isomerism” means compounds that have identicalmolecular formulae but differ in the sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereoisomers,” and stereoisomers that are non-superimposable mirrorimages of each other are termed “enantiomers” or sometimes opticalisomers. A mixture containing equal amounts of individual enantiomericforms of opposite chirality is termed a “racemic mixture.”

As used herein, the term “chiral center” refers to a carbon atom bondedto four nonidentical substituents.

As used herein, the term “chiral isomer” means a compound with at leastone chiral centre. Compounds with more than one chiral centre may existeither as an individual diastereomer or as a mixture of diastereomers,termed “diastereomeric mixture.” When one chiral centre is present, astereoisomer may be characterised by the absolute configuration (R or S)of that chiral centre. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral centre. Thesubstituents attached to the chiral centre under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511, Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

As used herein, the term “geometric isomer” means the diastereomers thatowe their existence to hindered rotation about double bonds or acycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

It is to be understood that the compounds of the present disclosure maybe depicted as different chiral isomers or geometric isomers. It is alsoto be understood that when compounds have chiral isomeric or geometricisomeric forms, all isomeric forms are intended to be included in thescope of the present disclosure, and the naming of the compounds doesnot exclude any isomeric forms, it being understood that not all isomersmay have the same level of activity.

It is to be understood that the structures and other compounds discussedin this disclosure include all atropic isomers thereof. It is also to beunderstood that not all atropic isomers may have the same level ofactivity.

As used herein, the term “tautomer” is one of two or more structuralisomers that exist in equilibrium and is readily converted from oneisomeric form to another. This conversion results in the formalmigration of a hydrogen atom accompanied by a switch of adjacentconjugated double bonds. Tautomers exist as a mixture of a tautomericset in solution. In solutions where tautomerisation is possible, achemical equilibrium of the tautomers will be reached. The exact ratioof the tautomers depends on several factors, including temperature,solvent and pH. The concept of tautomers that are interconvertible bytautomerisations is called tautomerism. Of the various types oftautomerism that are possible, two are commonly observed. In keto-enoltautomerism a simultaneous shift of electrons and a hydrogen atomoccurs. Ring-chain tautomerism arises as a result of the aldehyde group(—CHO) in a sugar chain molecule reacting with one of the hydroxy groups(—OH) in the same molecule to give it a cyclic (ring-shaped) form asexhibited by glucose.

It is to be understood that the compounds of the present disclosure maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present disclosure, and the naming ofthe compounds does not exclude any tautomer form. It will be understoodthat certain tautomers may have a higher level of activity than others.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric centre, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterised by the absolute configuration of itsasymmetric centre and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarised light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this disclosure may possess one or more asymmetriccentres; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001),for example by synthesis from optically active starting materials or byresolution of a racemic form. Some of the compounds of the disclosuremay have geometric isomeric centres (E- and Z-isomers). It is to beunderstood that the present disclosure encompasses all optical,diastereoisomers and geometric isomers and mixtures thereof that possessinflammasome inhibitory activity.

It is to be understood that the compounds of any Formula describedherein include the compounds themselves, as well as their salts, andtheir solvates, if applicable. A salt, for example, can be formedbetween an anion and a positively charged group (e.g., amino) on asubstituted compound disclosed herein. Suitable anions include chloride,bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate,citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate,glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate,salicylate, lactate, naphthalenesulfonate, and acetate (e.g.,trifluoroacetate).

As used herein, the term “pharmaceutically acceptable anion” refers toan anion suitable for forming a pharmaceutically acceptable salt.Likewise, a salt can also be formed between a cation and a negativelycharged group (e.g., carboxylate) on a substituted compound disclosedherein. Suitable cations include sodium ion, potassium ion, magnesiumion, calcium ion, and an ammonium cation such as tetramethylammonium ionor diethylamine ion. The substituted compounds disclosed herein alsoinclude those salts containing quaternary nitrogen atoms.

It is to be understood that the compounds of the present disclosure, forexample, the salts of the compounds, can exist in either hydrated orunhydrated (the anhydrous) form or as solvates with other solventmolecules. Nonlimiting examples of hydrates include monohydrates,dihydrates, etc. Nonlimiting examples of solvates include ethanolsolvates, acetone solvates, etc.

As used herein, the term “solvate” means solvent addition forms thatcontain either stoichiometric or non-stoichiometric amounts of solvent.Some compounds have a tendency to trap a fixed molar ratio of solventmolecules in the crystalline solid state, thus forming a solvate. If thesolvent is water the solvate formed is a hydrate; and if the solvent isalcohol, the solvate formed is an alcoholate. Hydrates are formed by thecombination of one or more molecules of water with one molecule of thesubstance in which the water retains its molecular state as H2O.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound.

As used herein, the term “derivative” refers to compounds that have acommon core structure and are substituted with various groups asdescribed herein.

It is also to be understood that certain compounds of any one of theFormulae disclosed herein may exist in solvated as well as unsolvatedforms such as, for example, hydrated forms. A suitable pharmaceuticallyacceptable solvate is, for example, a hydrate such as hemi-hydrate, amono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood thatthe disclosure encompasses all such solvated forms that possessinflammasome inhibitory activity.

It is also to be understood that certain compounds of any one of theFormulae disclosed herein may exhibit polymorphism, and that thedisclosure encompasses all such forms, or mixtures thereof, whichpossess inflammasome inhibitory activity. It is generally known thatcrystalline materials may be analysed using conventional techniques suchas X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry,Thermal Gravimetric Analysis, Diffuse Reflectance Infrared FourierTransform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy,solution and/or solid state nuclear magnetic resonance spectroscopy. Thewater content of such crystalline materials may be determined by KarlFischer analysis.

Compounds of any one of the Formulae disclosed herein may exist in anumber of different tautomeric forms and references to include all suchforms. For the avoidance of doubt, where a compound can exist in one ofseveral tautomeric forms, and only one is specifically described orshown, all others are nevertheless embraced by Formula (I). Examples oftautomeric forms include keto-, enol-, and enolate-forms, as in, forexample, the following tautomeric pairs: keto/enol (illustrated below),imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, and nitro/aci-nitro.

The compounds of any one of the Formulae disclosed herein may beadministered in the form of a prodrug which is broken down in the humanor animal body to release a compound of the disclosure. A prodrug may beused to alter the physical properties and/or the pharmacokineticproperties of a compound of the disclosure. A prodrug can be formed whenthe compound of the disclosure contains a suitable group or substituentto which a property-modifying group can be attached. Examples ofprodrugs include derivatives containing in vivo cleavable alkyl or acylsubstitutents at the ester or amide group in any one of the Formulaedisclosed herein.

Accordingly, the present disclosure includes those compounds of any oneof the Formulae disclosed herein as defined hereinbefore when madeavailable by organic synthesis and when made available within the humanor animal body by way of cleavage of a prodrug thereof. Accordingly, thepresent disclosure includes those compounds of any one of the Formulaedisclosed herein that are produced by organic synthetic means and alsosuch compounds that are produced in the human or animal body by way ofmetabolism of a precursor compound, that is a compound of any one of theFormulae disclosed herein may be a synthetically-produced compound or ametabolically-produced compound.

A suitable pharmaceutically acceptable prodrug of a compound of any oneof the Formulae disclosed herein is one that is based on reasonablemedical judgment as being suitable for administration to the human oranimal body without undesirable pharmacological activities and withoutundue toxicity. Various forms of prodrug have been described, forexample in the following documents. a) Methods in Enzymology, Vol. 42,p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b)Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) ATextbook of Drug Design and Development, edited by Krogsgaard-Larsen andH. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug DeliveryReviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal ofPharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem.Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs asNovel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E.Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press,1987.

A suitable pharmaceutically acceptable prodrug of a compound of any oneof the Formulae disclosed herein that possesses a hydroxy group is, forexample, an in vivo cleavable ester or ether thereof. An in vivocleavable ester or ether of a compound of any one of the Formulaedisclosed herein containing a hydroxy group is, for example, apharmaceutically acceptable ester or ether which is cleaved in the humanor animal body to produce the parent hydroxy compound. Suitablepharmaceutically acceptable ester forming groups for a hydroxy groupinclude inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters). Further suitable pharmaceuticallyacceptable ester forming groups for a hydroxy group include C₁-C₁₀alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substitutedbenzoyl and phenylacetyl groups, C₁-C₁₀ alkoxycarbonyl groups such asethoxycarbonyl, N,N—(C₁-C₆ alkyl)2carbamoyl, 2-dialkylaminoacetyl and2-carboxyacetyl groups. Examples of ring substituents on thephenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and4-(C₁-C₄ alkyl)piperazin-1-ylmethyl. Suitable pharmaceuticallyacceptable ether forming groups for a hydroxy group includeα-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethylgroups.

A suitable pharmaceutically acceptable prodrug of a compound of any oneof the Formulae disclosed herein that possesses a carboxy group is, forexample, an in vivo cleavable amide thereof, for example an amide formedwith an amine such as ammonia, a C₁₋₄alkylamine such as methylamine, a(C₁-C₄ alkyl)2-amine such as dimethylamine, N-ethyl-N-methylamine ordiethylamine, a C₁-C₄ alkoxy-C₂-C₄ alkylamine such as2-methoxyethylamine, a phenyl-C₁-C₄ alkylamine such as benzylamine andamino acids such as glycine or an ester thereof.

A suitable pharmaceutically acceptable prodrug of a compound of any oneof the Formulae disclosed herein that possesses an amino group is, forexample, an in vivo cleavable amide derivative thereof. Suitablepharmaceutically acceptable amides from an amino group include, forexample an amide formed with C₁-C₁₀ alkanoyl groups such as an acetyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.Examples of ring substituents on the phenylacetyl and benzoyl groupsinclude aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl,morpholinomethyl, piperazin-1-ylmethyl and 4-(C₁-C₄alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of any one of the Formulae disclosedherein may be exerted in part by one or more metabolites that are formedwithin the human or animal body after administration of a compound ofany one of the Formulae disclosed herein. As stated hereinbefore, the invivo effects of a compound of any one of the Formulae disclosed hereinmay also be exerted by way of metabolism of a precursor compound (aprodrug).

A suitable general route for the preparation of a compound of theapplication is using protocol A and can be described in Scheme 1 herein.

Examples presented herein, unless otherwise stated, are synthesizedaccording to the general procedure presented in Scheme 1.

Step 1 involves an SNAr reaction between an amine (i) and an aryldichloride (ii), to provide the target chloroaryl intermediate (iii).Step 2 involves cross-coupling between intermediate (iii) and thedesired boronic acids or boronates iv to generate the desired compoundv. Amines i, aryl dichlorides ii and boronic acids or boronates iv areeither commercially available or known in the chemical literature,unless otherwise indicated.

Another suitable general route for the preparation of a compound of theinstant disclosure is using protocol B in Scheme 2 herein.

Step 1 involves opening commercially available 3,4-pyridinedicarboxylicacid anhydride vi with a Grignard reagent to obtain carboxylic acid vii.Step 2 features chlorination, then condensation with hydrazine tofurnish pyridazinol viii. Step 3 then involves another chlorination tofurnish key intermediate ix, which in turn may be engaged in step 4 as aan SNAr reaction with an amine (i) to form azaphthalazines x. Step 5then features a methyl ether deprotection then provides analogs xi.

Biological Assays

Compounds designed, selected and/or optimised by methods describedabove, once produced, can be characterised using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterised by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules described herein for activity, using techniques known in theart. General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

Various in vitro or in vivo biological assays are may be suitable fordetecting the effect of the compounds of the present disclosure. Thesein vitro or in vivo biological assays can include, but are not limitedto, enzymatic activity assays, electrophoretic mobility shift assays,reporter gene assays, in vitro cell viability assays, and the assaysdescribed herein.

In some embodiments, the biological assay is described in the Examplesherein.

Pharmaceutical Compositions

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure as an activeingredient. In some embodiments, the present disclosure provides apharmaceutical composition comprising at least one compound of each ofthe formulae described herein, or a pharmaceutically acceptable salt orsolvate thereof, and one or more pharmaceutically acceptable carriers orexcipients. In some embodiments, the present disclosure provides apharmaceutical composition comprising at least one compound describedherein.

In one embodiment of the instant disclosure the pharmaceuticalcomposition comprises(R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenolas described herein and a pharmaceutically acceptable carrier.

In another embodiment of the disclosure, the pharmaceutical compositioncomprises5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenolas described herein and a pharmaceutically acceptable carrier.

In another embodiment of the disclosure, the pharmaceutical compositioncomprises(R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenolas described herein and a pharmaceutically acceptable carrier.

In another embodiment of the disclosure, the pharmaceutical compositioncomprises(S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenoldescribed herein and a pharmaceutically acceptable carrier.

In one embodiment of the instant disclosure the pharmaceuticalcomposition comprises(R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenolas described herein and a pharmaceutically acceptable carrier.

In one embodiment of the instant disclosure the pharmaceuticalcomposition comprises(S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenolas described herein and a pharmaceutically acceptable carrier.

The compounds of present disclosure can be formulated for oraladministration in forms such as tablets, capsules (each of whichincludes sustained release or timed release formulations), pills,powders, granules, elixirs, tinctures, suspensions, syrups andemulsions. The compounds of present disclosure on can also be formulatedfor intravenous (bolus or in-fusion), intraperitoneal, topical,subcutaneous, intramuscular or transdermal (e.g., patch) administration,all using forms well known to those of ordinary skill in thepharmaceutical arts.

The formulation of the present disclosure may be in the form of anaqueous solution comprising an aqueous vehicle. The aqueous vehiclecomponent may comprise water and at least one pharmaceuticallyacceptable excipient. Suitable acceptable excipients include thoseselected from the group consisting of a solubility enhancing agent,chelating agent, preservative, tonicity agent, viscosity/suspendingagent, buffer, and pH modifying agent, and a mixture thereof.

Any suitable solubility enhancing agent can be used. Examples of asolubility enhancing agent include cyclodextrin, such as those selectedfrom the group consisting of hydroxypropyl-β-cyclodextrin,methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin,ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin,peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin,hydroxyethyl-β-cyclodextrin,2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin,glucosyl-β-cyclodextrin, sulfated p-cyclodextrin (S-β-CD),maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether,branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomlymethylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixturesthereof.

Any suitable chelating agent can be used. Examples of a suitablechelating agent include those selected from the group consisting ofethylenediaminetetraacetic acid and metal salts thereof, disodiumedetate, trisodium edetate, and tetrasodium edetate, and mixturesthereof.

Any suitable preservative can be used. Examples of a preservativeinclude those selected from the group consisting of quaternary ammoniumsalts such as benzalkonium halides (preferably benzalkonium chloride),chlorhexidine gluconate, benzethonium chloride, cetyl pyridiniumchloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate,phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben,sorbic acid, potassium sorbate, sodium benzoate, sodium propionate,ethyl p-hydroxybenzoate, propylaminopropyl biguanide, andbutyl-β-hydroxybenzoate, and sorbic acid, and mixtures thereof.

The aqueous vehicle may also include a tonicity agent to adjust thetonicity (osmotic pressure). The tonicity agent can be selected from thegroup consisting of a glycol (such as propylene glycol, diethyleneglycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol,potassium chloride, and sodium chloride, and a mixture thereof.

The aqueous vehicle may also contain a viscosity/suspending agent.Suitable viscosity/suspending agents include those selected from thegroup consisting of cellulose derivatives, such as methyl cellulose,ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such aspolyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acidpolymers (carbomers), such as polymers of acrylic acid cross-linked withpolyalkenyl ethers or divinyl glycol (Carbopols—such as Carbopol 934,Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and amixture thereof.

In order to adjust the formulation to an acceptable pH (typically a pHrange of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5,particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), theformulation may contain a pH modifying agent. The pH modifying agent istypically a mineral acid or metal hydroxide base, selected from thegroup of potassium hydroxide, sodium hydroxide, and hydrochloric acid,and mixtures thereof, and preferably sodium hydroxide and/orhydrochloric acid. These acidic and/or basic pH modifying agents areadded to adjust the formulation to the target acceptable pH range. Henceit may not be necessary to use both acid and base—depending on theformulation, the addition of one of the acid or base may be sufficientto bring the mixture to the desired pH range.

The aqueous vehicle may also contain a buffering agent to stabilise thepH. When used, the buffer is selected from the group consisting of aphosphate buffer (such as sodium dihydrogen phosphate and disodiumhydrogen phosphate), a borate buffer (such as boric acid, or saltsthereof including disodium tetraborate), a citrate buffer (such ascitric acid, or salts thereof including sodium citrate), andε-aminocaproic acid, and mixtures thereof.

The formulation may further comprise a wetting agent. Suitable classesof wetting agents include those selected from the group consisting ofpolyoxypropylene-polyoxyethylene block copolymers (poloxamers),polyethoxylated ethers of castor oils, polyoxyethylenated sorbitanesters (polysorbates), polymers of oxyethylated octyl phenol(Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acidglyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters,and mixtures thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch: a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or aflavouring agent such as peppermint, methyl salicylate, or orangeflavoring.

According to a further aspect of the disclosure there is provided apharmaceutical composition which comprises a compound of the disclosureas defined hereinbefore, or a pharmaceutically acceptable salt, hydrateor solvate thereof, in association with a pharmaceutically acceptablediluent or carrier.

The compositions of the disclosure may be in a form suitable for oraluse (for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the disclosure may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

An effective amount of a compound of the present disclosure for use intherapy is an amount sufficient to treat or prevent an inflammasomerelated condition referred to herein, slow its progression and/or reducethe symptoms associated with the condition.

An effective amount of a compound of the present disclosure for use intherapy is an amount sufficient to treat an inflammasome relatedcondition referred to herein, slow its progression and/or reduce thesymptoms associated with the condition.

The size of the dose for therapeutic or prophylactic purposes of acompound disclosed herein will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well-known principles ofmedicine.

Methods of Use

In some aspects, the present disclosure provides a method of inhibitingNLRP3 activity (e.g., in vitro or in vivo), comprising contacting a cellwith an effective amount of a compound of the present disclosure or apharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides a method of treating orpreventing a disease or disorder inhibited by NLRP3 as disclosed hereinin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound of the present disclosureor a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the present disclosure.

In some aspects, the present disclosure provides a method of treating adisease or disorder disclosed herein in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of the presentdisclosure.

In some embodiments, the disease or disorder is a disease or disorder inwhich NLRP3 activity is implicated.

In some embodiments, the disease or disorder is inflammation, anauto-immune disease, a cancer, an infection, a disease or disorder ofthe central nervous system, a metabolic disease, a cardiovasculardisease, a respiratory disease, a kidney disease, a liver disease, anocular disease, a skin disease, a lymphatic disease, a rheumaticdisease, a psychological disease, graft versus host disease, allodynia,or an NLRP3-related disease in a subject that has been determined tocarry a germline or somatic non-silent mutation in NLRP3.

In some aspects, the present disclosure provides a method of treating orpreventing inflammation, an auto-immune disease, a cancer, an infection,a disease or disorder of the central nervous system, a metabolicdisease, a cardiovascular disease, a respiratory disease, a kidneydisease, a liver disease, an ocular disease, a skin disease, a lymphaticdisease, a rheumatic disease, a psychological disease, graft versus hostdisease, allodynia, or an NLRP3-related disease in a subject that hasbeen determined to carry a germline or somatic non-silent mutation inNLRP3 in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound of the presentdisclosure or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of the present disclosure.

In some aspects, the present disclosure provides a method of treatinginflammation, an auto-immune disease, a cancer, an infection, a diseaseor disorder of the central nervous system, a metabolic disease, acardiovascular disease, a respiratory disease, a kidney disease, a liverdisease, an ocular disease, a skin disease, a lymphatic disease, arheumatic disease, a psychological disease, graft versus host disease,allodynia, or an NLRP3-related disease in a subject that has beendetermined to carry a germline or somatic non-silent mutation in NLRP3in a subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound of the present disclosureor a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the present disclosure.

In some aspects, the present disclosure provides a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof for usein inhibiting NLRP3 activity (e.g., in vitro or in vivo).

In some aspects, the present disclosure provides a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof for usein inhibiting NLRP3 (e.g., in vitro or in vivo).

In some aspects, the present disclosure provides a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof for useas an antagonist for NLRP3 (e.g., in vitro or in vivo).

In some aspects, the present disclosure provides a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof for usein treating or preventing a disease or disorder disclosed herein.

In some aspects, the present disclosure provides a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof for usein treating a disease or disorder disclosed herein.

In some aspects, the present disclosure provides use of a compound ofthe present disclosure or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for inhibiting NLRP3 activity (e.g., invitro or in vivo).

In some aspects, the present disclosure provides use of a compound ofthe present disclosure or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for inhibiting NLRP3 (e.g., in vitro orin vivo). In some aspects, the present disclosure provides use of acompound of the present disclosure or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating or preventing adisease or disorder disclosed herein.

In some aspects, the present disclosure provides use of a compound ofthe present disclosure or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for treating a disease or disorderdisclosed herein.

Effectiveness of compounds of the disclosure can be determined byindustry-accepted assays/disease models according to standard practicesof elucidating the same as described in the art and are found in thecurrent general knowledge.

In some embodiments, the disease or disorder is inflammation, anauto-immune disease, a cancer, an infection, a disease or disorder ofthe central nervous system, a metabolic disease, a cardiovasculardisease, a respiratory disease, a kidney disease, a liver disease, anocular disease, a skin disease, a lymphatic disease, a rheumaticdisease, a psychological disease, graft versus host disease, allodynia,or an NLRP3-related disease in a subject that has been determined tocarry a germline or somatic non-silent mutation in NLRP3.

In some embodiments, the disease or disorder of the central nervoussystem is Parkinson's disease, Alzheimer's disease, traumatic braininjury, spinal cord injury, amyotrophic lateral sclerosis, or multiplesclerosis.

In some embodiments, the kidney disease is an acute kidney disease, achronic kidney disease, or a rare kidney disease.

In some embodiments, the skin disease is psoriasis, hidradenitissuppurativa (HS), or atopic dermatitis.

In some embodiments, the rheumatic disease is dermatomyositis, Still'sdisease, or juvenile idiopathic arthritis.

In some embodiments, the NLRP3-related disease in a subject that hasbeen determined to carry a germline or somatic non-silent mutation inNLRP3 is cryopyrin-associated autoinflammatory syndrome.

In some embodiments, the cryopyrin-associated autoinflammatory syndromeis familial cold autoinflammatory syndrome, Muckle-Wells syndrome, orneonatal onset multisystem inflammatory disease.

Routes of Administration

Compounds of the present disclosure, or pharmaceutically acceptablesalts thereof, may be administered alone as a sole therapy or can beadministered in addition with one or more other substances and/ortreatments. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of the individualcomponents of the treatment.

For example, therapeutic effectiveness may be enhanced by administrationof an adjuvant (i.e. by itself the adjuvant may only have minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the individual is enhanced).

Alternatively, by way of example only, the benefit experienced by anindividual may be increased by administering a compound of the instantdisclosure with another therapeutic agent (which also includes atherapeutic regimen) that also has therapeutic benefit.

In the instances where the compound of the present disclosure isadministered in combination with other therapeutic agents, the compoundof the disclosure need not be administered via the same route as othertherapeutic agents, and may, because of different physical and chemicalcharacteristics, be administered by a different route. For example, thecompound of the disclosure may be administered orally to generate andmaintain good blood levels thereof, while the other therapeutic agentmay be administered intravenously. The initial administration may bemade according to established protocols known in the art, and then,based upon the observed effects, the dosage, modes of administration andtimes of administration can be modified by the skilled clinician.

The particular choice of other therapeutic agent will depend upon thediagnosis of the attending physicians and their judgment of thecondition of the individual and the appropriate treatment protocol.According to this aspect of the disclosure there is provided acombination for use in the treatment of a disease in which inflammasomeactivity is implicated comprising a compound of the disclosure asdefined hereinbefore, or a pharmaceutically acceptable salt thereof, andanother suitable agent.

According to a further aspect of the disclosure there is provided apharmaceutical composition which comprises a compound of the disclosure,or a pharmaceutically acceptable salt thereof, in combination with asuitable, in association with a pharmaceutically acceptable diluent orcarrier.

In any of the above-mentioned pharmaceutical composition, process,method, use, medicament, and manufacturing features of the instantdisclosure, any of the alternate embodiments of macromolecules of thepresent disclosure described herein also apply.

The compounds of the disclosure or pharmaceutical compositionscomprising these compounds may be administered to a subject by anyconvenient route of administration, whether systemically/peripherally ortopically (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g. byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intra-arterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

Examples

For exemplary purpose, neutral compounds described herein aresynthesized and tested in the examples. It is understood that theneutral compounds disclosed herein may be converted to the correspondingpharmaceutically acceptable salts of the compounds using routinetechniques in the art (e.g., by saponification of an ester to thecarboxylic acid salt, or by hydrolyzing an amide to form a correspondingcarboxylic acid and then converting the carboxylic acid to a carboxylicacid salt).

Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz asstated and at 300.3 K unless otherwise stated; the chemical shifts (6)are reported in parts per million (ppm). Spectra were recorded using aBruker Avance 400instrument with 8, 16 or 32 scans.

LC-MS chromatograms and spectra were recorded using a ShimadzuLCMS-2020. Injection volumes were 0.7-8.0 μl and the flow rates weretypically 0.8 or 1.2 ml/min. Detection methods were diode array (DAD) orevaporative light scattering (ELSD) as well as positive ion electrosprayionisation. MS range was 100-1000 Da. Solvents were gradients of waterand acetonitrile both containing a modifier (typically 0.01-0.04%) suchas trifluoroacetic acid or ammonium carbonate.

Abbreviations

-   -   DMF N,N-dimethylformamide    -   DMSO dimethylsulfoxide    -   dppf 1,1′-bis(diphenylphosphino)ferrocene    -   ESI electrospray ionisation    -   EtOAc or EA ethyl acetate    -   EtOH ethanol    -   h hour(s)    -   HPLC high-performance liquid chromatography    -   LCMS Liquid Chromatography—Mass Spectrometry    -   MeCN or ACN acetonitrile    -   min minute(s)    -   mw microwave    -   m/z mass/charge    -   PE petroleum ether    -   prep-HPLC preparative high-performance liquid chromatography    -   rt room temperature    -   Y yield

Example 1.(R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol(Compound 1)

Step 1: Synthesis of1-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine and4-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-1-amine

Into a 5 mL microwave tube were added1,4-dichloropyrido[3,4-d]pyridazine (250 mg, 1.25 mmol, 1 equiv), DMF (3mL) and Na2CO3 (423.91 mg, 4.00 mmol, 3.2 equiv) at 130° C. The finalreaction mixture was irradiated with microwave radiation for 40 min at130° C. After the reaction was completed, the residue was purified byreverse flash chromatography with the following conditions: column, C18silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30 min;detector, UV 254 nm. The resulting mixture was concentrated underreduced pressure. This resulted in1-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine and4-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-1-amine (150mg, mixture of two isomers) as a yellow oil. LCMS: (ES, m/z): RT=0.735min, m/z=279[M+1]⁺.

Step 2:(R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol(Compound 1)

Into a 25 mL round-bottom flask were added a mixture of1-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine and4-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-1-amine (150mg, 0.53 mmol, 1 equiv), 4-chloro-2-hydroxyphenylboronic acid (120.59mg, 0.69 mmol, 1.3 equiv), Pd(dppf)Cl2 (78.75 mg, 0.10 mmol, 0.2 equiv),Na2CO3 (171.11 mg, 1.61 mmol, 3 equiv), dioxane (6 mL) and H2O (1.2 mL)at 80° C. The final reaction mixture took for 2 h at 80° C. After thereaction was completed, concentrated, the residue was purified byreverse flash chromatography with the following conditions: column, C18silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30 min;detector, UV 254 nm. After the reaction was completed, concentrated, thecrude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)); Column, XBridge Prep Phenyl OBD Column, 19*250 mm,5 μm; mobile phase, Water (10 mmol/L NH4HCO3) and ACN (25% ACN up to 45%in 12 min); Detector, UV 254 This resulted in5-chloro-2-{4-[(4,4-dimethyloxolan-3-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol(3.2 mg, 1.54%) as a light yellow crude solid and5-chloro-2-(4-{[-4,4-dimethyloxolan-3-yl]amino)pyrido[3,4-d]pyridazin-1-yl}phenol(32 mg, 15.4%) as a light yellow crude solid. Then Sent 20 mg of5-chloro-2-(4-{[-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenolfor chiral separation, the condition was Column, Chiral ARTCellulose-SA, 2*25 cm, 5 um; mobile phase, MtBE (0.1% FA)- andIPA:DCM=1:1-(hold 50% IPA:DCM=1:1—in 10 min); Detector, UV 254. Thisresulted in5-chloro-2-(4-{[(3R)-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol(5.4 mg, 2.69%) as a light yellow solid. This resulted in5-chloro-2-(4-{[(3S)-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol(6.0 mg, 3.00%) as a light yellow solid.

(R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

LCMS: (ES, m/z): RT=0.605 min, m/z=371[M+1]⁺. 1H NMR (400 MHz,Methanol-d4) δ 9.77 (d, J=1.0 Hz, 1H), 8.87 (d, J=5.7 Hz, 1H), 7.59-7.50(m, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.06 (d, J=7.8 Hz, 2H), 5.10-4.98 (m,1H), 4.47-4.30 (m, 1H), 3.99-3.86 (m, 1H), 3.75 (d, J=8.4 Hz, 1H), 3.68(d, J=8.4 Hz, 1H), 1.32 (s, 3H), 1.16 (s, 3H).

(S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

LCMS: (ES, m/z): RT=0.605 min, m/z=371[M+1]⁺. 1H NMR (400 MHz,Methanol-d4) δ 9.81-9.74 (m, 1H), 8.87 (d, J1=5.7 Hz, 1H), 7.57-7.51 (m,J H), 7.38 (d, J=8.0 Hz, 1H), 7.06 (d, J=7.7 Hz, 2H), 5.13-4.98 (m, 1H),4.50-4.33 (m, 1H), 4.00-3.87 (m, 1H), 2.45 (d, J=8.3 Hz, 1H), 2.08 (d,J=8.3 Hz, 1H), 1.32 (s, 3H), 1.16 (s, 3H).

Example 2.5-chloro-2-(4-{[(1S,2S)-2-hydroxycyclopentyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol)(compound 14)

Step 1: Synthesis of(1S,2S)-2-((1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

To a stirred solution of furo[3,4-c]pyridine-1,3-dione (30.0 g, 201.20mmol, 1.00 equiv) and tetrahydrofuran (300 mL) was addedbromo(4-chloro-2-methoxyphenyl)magnesium (0.5M in THF) (241 mL, 120mmol, 0.60 equiv) dropwise at −78° C. under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at 25° C. under nitrogenatmosphere. The reaction progress was monitored by LCMS. The reactionwas quenched by the addition of water (150 mL) at 0° C. The precipitatedsolids were collected by filtration and washed with water (3×50 mL).This resulted in 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid(20 g, yield=34.08%) as a light brown solid. LCMS (ES, m/z): RT=0.662min, m/z=292.0[M+1]⁺.

Step 2: Synthesis of1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol

Into a 250 mL round-bottom flask were added4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (5.00 g, 17.1mmol, 1.00 equiv) and SOCl₂ (50 mL). The resulting mixture was stirredfor 2 h at 70° C. The reaction was monitored by TLC. After the reactionwas completed, the resulting mixture was concentrated under vacuum. Theresidue was dissolved in DCM (50 mL) and added into the solution ofNH₂NH₂·H₂O (3.43 g, 68.6 mmol, 4.00 equiv), MeOH (50 mL) at 0° C. Theresulting mixture was stirred for 3 h at 70° C. in an oil bath. Thereaction progress was monitored by LCMS. The precipitated solids werecollected by filtration. The crude product (4 g, purity=90%) waspurified by Prep-HPLC with the following conditions (2 #SHIMADZU(HPLC-01)): Column, XBridge Shield RP18 OBD Column, 19*250 mm, 10 μm;mobile phase, water (10 mmol/L NH4HCO3) and ACN (hold 39% ACN in 17min); Detector, UV 254/220 nm. This resulted in1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.0 g,yield=40.6%) as a off-white solid. LCMS: (ES, m/z): RT=0.723 min,m/z=288.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 9.50 (s,1H), 8.94 (d, J=5.5 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.33 (d, J=1.9 Hz,1H), 7.23-7.15 (m, 2H), 3.75 (s, 3H).

Step 3: Synthesis of4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine

Into a 250 mL round-bottom flask were added1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.5 g, 8.69mmol, 1.00 equiv) and POCl₃ (40 mL), Pyridine (4 mL). The resultingmixture was stirred for 3 h at 100° C. The reaction progress wasmonitored by LCMS. The reaction was quenched with 500 ml of sodiumbicarbonate (aq.) and 500 ml of EtOAc at 0° C. The resulting mixture wasextracted with EtOAc (3×500 mL). The combined organic layers were driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. This resulted in4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (1.5 g,yield=56.38%) as a brown solid. LCMS (ES, m/z): RT=0.845 min,m/z=306.0[M+1]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.84-9.68 (m, 1H), 9.12 (d,J=5.7 Hz, 1H), 7.60-7.56 (m, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.41 (d, J=1.9Hz, 1H), 7.32-7.25 (m, 1H), 3.74 (s, 3H).

Step 4:1-(4-chloro-2-methoxyphenyl)-N-(3,3-dimethyltetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine(compound 3)

Into a 40 mL vial were added4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (200 mg,0.65 mmol, 1 equiv) and 3,3-dimethyloxan-4-amine (101.28 mg, 7.84 mmol,1.2 equiv), TEA (198.32 mg, 1.96 mmol, 3 equiv), DMSO (5 mL) at roomtemperature. The resulting mixture was stirred for overnight at 80° C.under nitrogen atmosphere. The reaction progress was monitored by LCMS.The resulting mixture was used in the next step directly without furtherpurification. LCMS: (ES, m/z): RT=0.684 min, m/z=399[M+1]⁺.

Step 5:1-(4-chloro-2-methoxyphenyl)-N-(3,3-dimethyltetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine

Into a 20 vial were added the reaction mixture from VTT-4546-1 and(ethylsulfanyl)sodium (1054.30 mg, 12.53 mmol, 25 equiv), DMSO (8 mL) atroom temperature. The resulting mixture was stirred for 2 h at 120° C.under nitrogen atmosphere. The reaction progress was monitored by LCMS.The resulting mixture was filtered, the filter cake was washed with MeCN(3×5 mL). The filtrate was concentrated under reduced pressure. Theresidue was purified by reverse flash chromatography with the followingconditions: column, C18 gel; mobile phase, MeCN in Water (10 mmol/LNH₄HCO₃), 0% to 100% gradient in 30 min; detector, UV 254 nm. Thisresulted in product as an off-white solid. The product (90 mg,purity=98.2%) was purified by Prep-HPLC with the following conditions(Prep-HPLC-064): Column, CHIRALPAK IG, 2*25 cm, 5 um; mobile phase, Hex-and MeOH:DCM=1:1— (hold 50% MeOH:DCM=1:1—in 23 min); Detector, UV 254 nmto afford5-chloro-2-(4-{[(4R)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol(27.8 mg, yield=14.29%) as an off-white solid and5-chloro-2-(4-{[(4S)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol(24.4 mg, yield=12.49%) as an off-white solid.

5-chloro-2-(4-{[(4R)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol(Compound 3)

LCMS: (ES, m/z): RT=0.553 min, m/z=385 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6)δ 10.24 (s, 1H), 9.89 (s, 1H), 8.86 (d, J=5.6 Hz, 1H), 7.38-7.20 (m,3H), 7.03 (d, J=7.4 Hz, 2H), 4.81-4.70 (m, 1H), 4.05-3.89 (m, 1H),3.54-3.42 (m, 2H), 3.25 (d, J1=11.3 Hz, 1H), 1.99-1.90 (m, 1H),1.75-1.66 (m, 1H), 1.14 (s, 3H), 0.87 (s, 3H).

5-chloro-2-(4-{[(4S)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol

LCMS: (ES, m/z): RT=0.671 min, m/z=385 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d4)δ 10.24 (s, 1H), 9.88 (s, 1H), 8.86 (d, J=5.6 Hz, 1H), 7.40-7.17 (m,3H), 7.03 (d, J=7.5 Hz, 2H), 4.80-4.72 (m, 1H), 4.05-3.96 (m, 1H),3.56-3.41 (m, 2H), 3.23 (s, 1H), 2.01-1.92 (m, J=12.2, 4.8 Hz, 1H),1.73-7.65 (m, 1H), 1.13 (s, 3H), 0.87 (s, 3H).

Table 1 shows the protocol by which the compounds of the instantdisclosure were prepared.

TABLE 1 MS (ESI; Cmp. m/z; # Structure M + H) Protocol 1

371.1 A (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 2

378.2 A 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1- yl)phenol 3

385.2 B (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4- d]pyridazin-1-yl)phenol 4

385.1 B (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4- d]pyridazin-1-yl)phenol 5

351.1 A (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin- 1-yl)-5-methylphenol 6

420.2 A (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol 7

420.2 A (S)-5-chloro-2-(4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 8

357.0 A 5-chloro-2-(4-(((1- (hydroxymethyl)cyclopropyl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

1H NMR table Cmp. # ¹H NMR 1 1H NMR (400 MHz, Methanol-d4) δ 9.77 (d, J= 1.0 Hz, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.59−7.50 (m, 1H), 7.38 (d, J =8.0 Hz, 1H), 7.06 (d, J = 7.8 Hz, 2H), 5.10−4.98 (m, 1H), 4.47−4.30 (m,1H), 3.99−3.86 (m, 1H), 3.75 (d, J = 8.4 Hz, 1H), 3.68 (d, J = 8.4 Hz,1H), 1.32 (s, 3H), 1.16 (s, 3H). 2 ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s,1H), 9.84 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 7.69 (t, J = 6.0 Hz, 1H),7.47 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 5.6 Hz, 1H), 7.26−6.90 (m, 3H),3.82 (d, J = 5.9 Hz, 2H), 1.25 (s, 6H). 3 ¹H NMR (400 MHz, DMSO-d₆) δ10.24 (s, 1H), 9.89 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 7.38−7.20 (m,3H), 7.03 (d, J = 7.4 Hz, 2H), 4.81−4.70 (m, 1H), 4.05−3.89 (m, 1H),3.54−3.42 (m, 2H), 3.25 (d, J = 11.3 Hz, 1H), 1.99−1.90 (m, 1H),1.75−1.66 (m, 1H), 1.14 (s, 3H), 0.87 (s, 3H). 4 ¹H NMR (400 MHz,Methanol-d₄) δ 9.70 (s, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.56−7.50 (m,1H), 7.38 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 4.80−4.71 (m,1H), 3.95−3.80 (m, 2H), 2.23−2.10 (m, 2H), 1.70−1.57 (m, 2H), 1.40 (s,3H), 1.31 (s, 3H). 5 ¹H NMR (400 MHz, Methanol-d₄) δ 9.70 (d, J = 1.0Hz, 1H), 8.85 (d, J = 5.7 Hz, 1H), 7.57 (m, J = 5.7, 1.0 Hz, 1H), 7.28(d, J = 7.7 Hz, 1H), 6.91−6.83 (m, 2H), 5.05−4.97 (m, 1H), 4.41 (m J =9.1, 6.7 Hz, 1H), 3.92 (m, J = 9.1, 5.9 Hz, 1H), 2.45 (m, J = 12.8, 8.1Hz, 1H), 2.40 (s, 3H), 2.08 (m, J = 12.7, 6.8 Hz, 1H), 1.45 (s, 3H),1.35 (s, 3H). 6 ¹H NMR (400 MHz, Methanol-d₄) δ 9.66 (s, 1H), 8.87 (d, J= 5.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H), 7.34(d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 4.03 (t, J = 8.0 Hz, 1H), 3.99−3.92(m, 1H), 3.87 (dd, J = 13.8, 4.7 Hz, 1H), 3.82−3.65 (m, 2H), 3.00 (d, J= 11.4 Hz, 1H), 2.74 (d, J = 11.7 Hz, 1H), 2.34 (s, 3H), 2.23 (td, J =11.7, 3.4 Hz, 1H), 2.04 (t, J = 10.9 Hz, 1H). 7 ¹H NMR (400 MHz,DMSO-d₆) δ 9.82 (s, 1H), 8.87 (d, J = 5.6 Hz, 1H), 7.94 (d, J = 5.8 Hz,1H), 7.43−7.27 (m, 2H), 7.04 (d, J = 7.1 Hz, 2H), 4.87-4.80 (m, 1H),4.11−3.91 (m, 2H), 3.85−3.72 (m, 2H), 2.40−2.26 (m, 1H), 2.22−2.06 (m,1H). 8 ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (d, J = 0.9 Hz, 1H), 9.13 (d, J= 5.5 Hz, 1H), 7.67−7.65 (m, 1H), ,7/40 (d, J = 8.1 Hz, 1H), 7.18−7.02(m, 2H), 3.77 (s, 2H), 3.62 (s, 2H), 0.86−0.63 (m, 4H).

Example 3. Biological Activity of the Compounds of the PresentDisclosure

The biological activity of the compounds of the present disclosure wasdetermined utilising the assay described herein.

Human Whole Blood—NLRP3

Heparin lithium coated tubes were used to collect blood from volunteers.Blood samples were distributed on 96 well plates using 90 μl per well.Priming was performed by adding 5 μl of LPS (O26:B6; Sigma L-2654) at afinal concentration of 1 μg/ml for 4.5 hours in a humidified incubatorwith 37° C., 5% CO2. Thirty minutes prior to NLRP3 activation, 5 μl of a20× compound solution or vehicle (2% DMSO) was added to each well andplates were incubated on a shaker (450 rpm) in a humidified incubatorwith 37° C., 5% CO2. Activation was then performed by adding 3.3 μl of a31X ATP solution per well. At the end of the 30 minutes stimulation, theplates were centrifuged (800 g, 10 min, room temperature) and the plasmafrom each well was frozen at −80° C. IL-1β levels in the supernatantwere analyzed using a mesoscale discovery assay (MSD K151TUK) accordingto the manufacturers' instructions. Human whole blood was drawn fromhealthy volunteers after obtaining written informed consent.

Table 2 assigns each compound a code for potency in the Human wholeblood (hWB) NLRP3 Assay: A or B. According to the code, A represents anIC₅₀ value ≤1.0 μM; B represents an IC₅₀ value >1.0 μM.

TABLE 2 Cmp. # hWB IC₅₀ 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A

Brain Levels (kp and kpu,u)—NLRP3

The in vivo total brain to plasma ratio was assessed in CD1 mice afteroral administration of the compound. Blood was collected at severaltimepoints up to 24 h, and transferred into plastic micro centrifugetubes with EDTA-K2 as anticoagulant. Blood samples were centrifuged at4000 g for 5 minutes at 4° C. to obtain plasma, then immediately frozenand stored at −75±15° C. prior to analysis. Animals were terminallyanaesthetized with a rising concentration of CO2 gas at about 1 minute.At selected timepoints, whole brains were removed from the skull, rinsedin cold PBS to remove blood, dried with clean gauze, then frozen inliquid nitrogen and kept at −75±15° C. before analysis. At the time ofanalysis, brain samples were homogenized with PBS by tissue weight (g)to PBS volume (mL) ratio 1:3. Plasma and brain drug levels werequantified by LC/MS/MS on a AB Sciex Triple Quad 5500+ instrument, afterseparation on a HALO 160A ES-C18, 2.7 μm 2.1×50 mm column. Quantitationwas performed using a calibration curve prepared in blank plasma orblank brain homogenate. The software WinNonlin (Phoenix™) was used forpharmacokinetic analysis from the concentrations versus time data,including the AUC_(inf) and AUC_(last). The Kp ratio (total brainconcentration over total plasma concentration) was calculated as(AUC_(tot,br))/(AUC_(tot,pl).)

The unbound brain exposure was assessed as Kp_(uu), which is the freebrain/free plasma concentration ratio (C_(u,br)/C_(u,pl)). TheC_(u,br)/C_(u,pl) ratios were obtained from in vivo total brain toplasma ratios (C_(tot,br)/C_(tot,pl)) by using in vitro determinedF_(u,br) and F_(u,pl).

Plasma protein binding and brain homogenate protein binding weremeasured by equilibrium dialysis in a HTDialysis plate. The dialysismembranes were soaked in ultrapure water for 60 minutes to separatestrips, then in 20% ethanol for 20 minutes, finally in dialysis bufferfor 20 minutes. The dialysis set up was assembled according to themanufacturer's instruction. Each cell received 150 μL of plasma or brainhomogenate spiked with 1 μM of compound, and dialyzed against an equalvolume of dialysis buffer (PBS). The dialysis plate was sealed andincubated in an incubator at 37° C. with 5% CO2 at 100 rpm for 6 hours.At the end of incubation, compound concentration was measured in bothchambers by LC-MS/MS on a Triple Quad™ 5500 from AB Inc after separationon a XSelect Hss T3 2.5p (2.1×30 mm) column. Free fraction (Fu) wascalculated as (Peak Area Ratio buffer chamber/Peak Area Ratio plasmachamber).

Finally, Kp_(uu) was calculated as (AUC_(tot,br)×F_(u,br))/(AUC_(tot,pl)×F_(u,pl)).

Table 3 assigns each compound a code for kp and kpu,u values: A or B.According to the code, A represents a value of >0.3 and B represents avalue of <0.3. The kp values were calculated by measuring whole braindrug levels over 24 h (AUC) in mice dosed at 20 mpk PO, and dividing byplasma AUC. The kpu,u was then calculated upon correcting this kp valuewith mouse plasma protein binding and mouse brain homogenates binding.

TABLE 3 Cmp. # kp kpu, u 1 A A 2 A A 3 A A 4 A A 5 A A 6 A A 7 B B 8 B B

Section 4—Important Structural and Biological Activity Comparisons withU.S. Ser. No. 17/528,928

The compounds described in the present invention are useful for thetreatment of NLRP3 proteins-mediated diseases and/or disorders and arestructurally related to compounds previously disclosed in U.S. patentapplication Ser. No. 17/528,928 as inhibitors of the same NLRP3proteins. The brain levels of these active pharmaceutical ingredient,however, were unexpected, and hence not contemplated in the U.S. Ser.No. 17/528,928 application. Thus, the unanticipated ability of theinstant compounds to penetrate the brain blood barrier constitutes anovel invention. Furthermore, as shown above in the data of Table 3 itis not obvious that inhibitors of NLPR3 proteins described in theapplication Ser. No. 17/528,928 exhibit this unpredicted activity. Theselected NLPR3 inhibitors of the instant disclosure were found toexhibit more potent brain-penetrant properties in a head-to-headcomparison with compounds of the U.S. Ser. No. 17/528,928 applicationsimilar in NLPR3 inhibitory activity in the blood as illustrated inTable 2. By way of a clearer illustration in Table 3, Compounds 1-6 ofthe present invention exhibit unexpected “A” brain levels contrary toCompounds 7 and 8 of U.S. Ser. No. 17/528,928 which exhibit “B” brainlevels and are not brain penetrant, thereby making the compounds of theinstant application more available to treatment of NLPR3-mediated CNSdiseases.

EQUIVALENTS

The details of one or more embodiments of the disclosure are set forthin the accompanying description above. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, the desired methodsand materials are herein described. Other features, objects, andadvantages of the disclosure will be apparent from the description andfrom the claims. In the specification and the appended claims, thesingular forms include plural referents unless the context clearlydictates otherwise. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this disclosurebelongs. All patents and publications cited in this specification areincorporated by reference.

The foregoing description has been presented only for the purposes ofillustration and is not intended to limit the disclosure to the preciseform disclosed, but by the claims appended hereto.

1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate,stereoisomer, prodrug, and/or isotopic derivative thereof. 2-7.(canceled)
 8. A pharmaceutical composition comprising a compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, clathrate,hydrate, stereoisomer, prodrug, and/or isotopic derivative thereof, anda pharmaceutically acceptable carrier, diluent, or excipient. 9-14.(canceled)
 15. A method of treating or preventing an NLRP3-relateddisease or disorder in a subject in need thereof, the method comprisingadministering to the subject a compound selected from:

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate,stereoisomer, prodrug, and/or isotopic derivative thereof.
 16. Themethod of claim 15, wherein the NLRP3-related disease or disorder isinflammation, an auto-immune disease, a cancer, an infection, a diseaseor disorder of the central nervous system, a metabolic disease, acardiovascular disease, a respiratory disease, a kidney disease, a liverdisease, an ocular disease, a skin disease, a lymphatic disease, arheumatic disease, a psychological disease, graft versus host disease,allodynia, or an NLRP3-related disease in a subject that has beendetermined to carry a germline or somatic non-silent mutation in NLRP3.17.-22. (canceled)
 23. A method of treating or preventing anNLRP3-related disease or disorder in a subject in need thereof, thedisease or disorder selected from the group consisting of Parkinson'sdisease, Alzheimer's disease, multiple sclerosis, refractory epilepsy,stroke, amyotropic lateral sclerosis, headache/pain, and traumatic braininjury, said method comprising administering to the subject a compoundselected from:

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate,stereoisomer, prodrug, and/or isotopic derivative thereof. 24.-30.(canceled)
 31. A method of preparing a compound of claim 1, or apharmaceutically acceptable salt, solvate, clathrate, hydrate,stereoisomer, prodrug, and/or isotopic derivative thereof, comprisingone or more steps described in Scheme 1 or Scheme 2.